Orally administered pharmaceutical preparation comprising liposomically encapsulated paclitaxel

ABSTRACT

The invention relates to pharmaceutical preparations suitable for oral application of liposomally encapsulated Taxol, its derivatives and Taxan. Preferably, they additionally contain at least one immuno-modulator, preferably Cyclosporine, and/or at least one cytokine, preferably PEG cytokines.

The invention relates to pharmaceutical preparations suitable for oralapplication of liposomally encapsulated taxol, its derivatives andtaxan. Fields of application of the invention are medicine and thepharmaceutical industry.

Taxol (chemically: paclitaxel) is a natural agent occurring in the barkof various species of yews (taxaceae) and can be obtained from thesebarks and also by chemical synthesis [J. Amer. Chem. Soc.,1110:5917-5919 (1988)]. Taxol supports the aggregation of themicrotubuli from tubulindimers and stabilises the microtubuli byinhibiting their depolymerisation. In addition, there is an abnormalarrangement and bundling of microtubuli during the entire cell cycle,which leads to formation of multiple microtubular division stars duringthe mitosis and thus to the inhibition of the normal dynamicreorganisation of the microtubular network. As the vital cell functionin the interphase and during the mitosis is decisively influenced bythis, Taxol shows a distinct anti-neoplastic activity against varioustumours, inter alia against implanted B16 melanoma, P388 leukaemia andagainst human mamma tumours.

However, the applicability of Taxol is greatly limited due to its lowwater-solubility. Although solution mediators such as Cremophor(poly-ethoxylated castor oil) and alcohol improve the solubility, theyalso lead to considerable side-effects in the application, e.g. toanaphylactic reactions. Dilution with a physiological saline solutionfor the application has the disadvantage that taxol does not havesufficient stability (maximum of 24 hours) in a physiological salinesolution. A dose-limiting side-effect is the myelo-suppression,primarily the neutropaenia [Semin. Oncol. 19:646-662 (1992)]. Liposomesprovide the possibility of including and incorporating bothwater-soluble and lipid-soluble substances due to their amphiphilecharacter.

Taxol as an almost water-insoluble substance can be dissolved with highefficiency in the lipid phase by liposomes of a suitable composition,which can be used for the treatment of various kinds of tumours andlocalisations. In a study, taxol was tested with regard to itsanti-tumour activity in a free and a liposomal form on two humanglioblastoma in a nude model (12.5 mg/kg/4 days). Both forms led to asignificant reduction of the growth of the tumour [In-Vivo 6 (1):23-7(1992)].

In WO 93/18751, the encapsulation of Taxol in liposomes and the use ofthe products obtained for treatment of cancer diseases is described. Acombination of this treatment with hyperthermia is preferred. The taxolliposomes produced manifest an improved stability. From DE 44 30 593 C2,a high-pressure homogenisation method for the production of liposomallyencapsulated taxol is known, with the liposomes manifesting a high shareof taxol and high stability.

Taxol can be outstandingly used as a cytostatic, although itsapplication is limited to parenteral preparations. An effectivity oftaxol in oral application has yet to be established internationally.Peroral forms of application for liposomally encapsulated taxol are alsonot known as yet.

It was surprisingly found that pharmaceutical preparations ofliposomally encapsulated taxol can be used for oral application andmanifest a good and fast, if applicable retarding effectivity in theseforms of application. This effectivity was increased even further if theoral forms of application contain not only liposomally encapsulatedtaxol, but also at least one immuno-modulator and/or at least onecytokine. Derivatives of taxol and taxan are also effective.

As can be seen from the enclosed figure, Taxol was applied as a 50 mgbolus in an oral form of administration and the effectivity of the agentdetermined on the basis of the tumour mass (ovarian carcinoma (human) ona nude mouse).

Application A was used as a control, an influence on the tumour mass wasnot established. B and C show the effectivity of unencapsulated taxol(B) and of unencapsulated taxol in combination with Cyclosporin A afteroral application, with the tumour mass hardly being reduced.

D shows the effectivity after oral application of liposomallyencapsulated taxol, the tumour mass being reduced significantly.

E, which shows the effectivity of the oral application of liposomallyencapsulated taxol in combination with Cyclosporin A, led to thedisappearance of the tumour.

The preferred dosage for liposomally encapsulated taxol is 1×50 mg/kgbody weight per day. The dosage of Cyclosporin is 5×50 mg/kg body weightper day.

The invention is implemented according to the claims.

1. A pharmaceutical preparation for oral administration, thepharmaceutical preparation comprising at least one active ingredientselected from the group consisting of paclitaxel (taxol), a derivativethereof, and taxans wherein a high share of the at least one activeingredient is encapsulated in a mixture of membrane-forming amphiphiles;in which the active ingredient was dissolved, and with addition of awatery phase, this mixture being subjected to high-pressurehomogenisation or ultrasound.
 2. The use of liposomally encapsulatedpaclitaxel (taxol), its derivatives or taxan for the production of adrug for oral administration in tumour therapy.
 3. The pharmaceuticalpreparation of claim 1, further comprising at least oneimmuno-modulator, preferably Cyclosporine, and/or at least one cytokine.4. The pharmaceutical preparation of claim 1, further comprisingpharmaceutical ancillaries and additives customary in the art.
 5. Thepharmaceutical preparation of claim 1, wherein the liposomes manifestingencapsulated taxol with a high share of taxol comprise a) a natural,semi-synthetic or fully synthetic amphiphile b) a steroid c) a chargedlipid component and/or a saturated lipid component and/or an ether lipidcomponent, and d) a carrier fluid and, if applicable, additionalancillaries.
 6. The pharmaceutical preparation of claim 5, wherein theamphiphile in a) is selected from the group consisting of a lipid,tenside, emulsifier, polyethylene glycol (PEG) and lipid PEG.
 7. Thepharmaceutical preparation of claim 6, wherein amphiphile has thegeneral formula I,

in which R₁ and R₂═C₁₀-C₂₀-alkanoyl, alkenoyl, alkyl, alkenyl.
 8. Thepharmaceutical preparation of claim 5, wherein the steroid is selectedfrom the group consisting of cholesterol, diethoxy-cholesterol andsitosterol.
 9. The pharmaceutical preparation of claim 5, wherein thecharged lipid component of (c) is selected from the group consisting ofan anion of dicethyl phosphate, of palmitine acid, of stearic acid, theanion of a phospholipid, the anion of a sphingolipid, and an anion ofpolyethylene glycol (PEG) is used as the charged lipid component. 10.The pharmaceutical preparation of claim 5, wherein the component (c) isselected from the group consisting of phosphatidylserine, phosphatideacid, phosphatidylglycerol and sulphatide.
 11. The pharmaceutical ofclaim 5, wherein component (c) is phosphatidylcholine.
 12. Thepharmaceutical preparation of claim 5, wherein component (c) is eitherdipalmitoylphosphatidylcholine or dimyristoylphosphatidylcholine. 13.The pharmaceutical preparation of claim 5, wherein component (d)comprises nanoparticles.
 14. The pharmaceutical preparation of claim 1,wherein the high pressure homogenization is performed at 50 to 1600 bar15. The pharmaceutical preparation of claim 3, wherein the cytokine is aPEG-cytokine.
 16. The pharmaceutical preparation of claim 5, wherein thecomponent (c) is a chemically modified phosphatidylethanolamine to whichproteins may be coupled.
 17. The pharmaceutical preparation of claim 5,wherein the component (c) is an ether lipid.
 18. The pharmaceuticalpreparation of claim 11, wherein the component (c) is eggphosphatidylcholine.